Disclosed is a method for the treatment of mania in bipolar disorder using derivatives of valproic acid and 2-valproenic acid amides.
Affective disorders refer mainly to changes in mood rather than thought disturbances (Rang, H. P., M. M. Dale and J. M. Ritter). Depression is the most common manifestation, although it also includes mania. In many respects the symptoms of mania are opposite to those of depression. Whereas the symptoms of depression include a feeling of misery, apathy, and low self-esteem, those of mania include excessive exuberance, enthusiasm and self-confidence. There are two basic types of depressive syndrome: bipolar and unipolar (Rang, H. P., M. M. Dale and J. M. Ritter). Patients with a history of both depression and mania are considered to have a bipolar disorder (BPD). Those patients which suffer from depression are considered to be unipolar. Bipolar disorder is further subdivided into different segments. In bipolar I patients have at least one manic episode with or without depression. In bipolar II patients have at least one hypomanic episode with depression. Patients with BPD have the highest rate of suicide among patients with psychiatric illnesses.
Anti-depresants are the standard treatment for unipolar depression, but are not effective for mania. To treat mania in bipolar depression lithium (Li+) has classically been used, and more recently the anti-epileptic drug (AED) valproate has been demonstrated to be effective (Bowden et al.; Calabrese, J. R. et al.) Other AEDs, such as carbamazepine, are also considered to be useful for mania. However phenobarbital, although clearly an effective AED, is not useful as a drug to treat mania (Belmaker, R. H. and Y. Yaroslavsky), or affective disorders. Today, many patients with mania are not controlled by current treatments (Calabresse, J. R. et al.). Therefore, there is a need for new treatments.
In order to discover new drugs in this area, rodent models relevant to the manic phase are used. One commonly used model is the amphetamine-induced hyperactivity model (Lyon, M.). This model focuses on an induced increase in the activity level of the animal (hyperactivity) as a parallel to the hyperactivity of the manic patient. The reversal of the induced hyperactivity in rodents, by pretreatment with a drug indicates the possible efficacy of this drug in the treatment of human mania. The most consistent finding with Li+ (the standard drug for mania) in untreated animals, is the reduction in rearing (Johnson, F. N.). Rearing is followed in the models by observing the vertical activity of the animals.
Bialer et al. describe a series of derivatives of valproic acid amides and 2-valproenic acid for the effective treatment of epilepsy and other neurological disorders (U.S. Pat. No. 5,585,358).
It has been surprisingly observed that the valproic acid amide of Bialer et al. (U.S. Pat. No. 5,585,358), Compound 1 below, decreases amphetamine-induced hyperactivity. The subject invention provides a method for the treatment of mania in bipolar disorder using derivatives of valproic acid amides and 2-valproenic acid amides.
The subject invention provides a method of treating mania in bipolar disorders in a subject. The invention comprises the administration of a therapeutically effective amount of a derivative of a valproic acid amide or a 2-valproenic acid amide having one of the following structures: 
wherein R1, R2, and R3 are independently the same or different and are hydrogen, a C1-C6 alkyl group, an aralkyl group, or an aryl group, and n is an integer which is greater than or equal to 0 and less than or equal to 3, or a compound containing a valproic or a 2-valproenic moiety, as well as pharmaceutical compositions comprising these derivatives or compounds.